Trileptal 150mg. 300mg. 600mg Tablet / Suspension

TRILEPTAL is indicated for the treatment of partial seizures with or without secondary generalised seizures and generalised tonic-clonic seizures, in adults and in children aged 1 month and above. TRILEPTAL may be used as monotherapy or adjunctive therapy in adults and in children of 1 month of age and above.

TRILEPTAL is suitable for use either as monotherapy or in combination with other anti-epileptic medicinal products. In mono- and adjunctive therapy, treatment with TRILEPTAL is initiated with a clinically effective dose given in two divided doses. The dose may be increased depending on the clinical response of the patient. When other antiepileptic medicinal products (AEMPs) are replaced by TRILEPTAL, the dose of the concomitant AEMP(s) should be reduced gradually on initiation of TRILEPTAL therapy. In adjunctive therapy, as the total antiepileptic medicinal products load of the patient is increased, the dose of concomitant AEMP(s) may need to be reduced and/or the TRILEPTAL dose increased more slowly (see section u2019 INTERACTIONS u2019) TRILEPTAL can be taken with or without food.

Known hypersensitivity to TRILEPTAL or to any of the excipients.

Hypersensitivity: Class I (immediate) hypersensitivity reactions including rash, pruritus, urticaria, angioedema and reports of anaphylaxis have been received in the post-marketing period. Cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of TRILEPTAL. If a patient develops these reactions after treatment with TRILEPTAL, the drug should be discontinued and an alternative treatment started. Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25-30 % of these patients may experience hypersensitivity reactions with TRILEPTAL (see u201cSide - effectsu201d). Hypersensitivity reactions, including multi-organ hypersensitivity reactions, may also occur in patients without a history of hypersensitivity to carbamazapine. Such reactions can affect the skin, liver, blood and lymphatic system or other organs, either individually or together in the context of a systemic reaction (see u201cSide - effectsu201d). If signs and symptoms suggestive of hypersensitivity reactions (e.g. severe skin reactions) occur, TRILEPTAL should be withdrawn immediately.

Dermatological effects: Serious dermatological reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyellu2019s syndrome) and erythema multiforme, have been reported very rarely in association with TRILEPTAL use. Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and very rarely be fatal. TRILEPTAL associated cases occurred in both children and adults. The median time to onset was 19 days. Several isolated cases of recurrence of the serious skin reaction when rechallenged with TRILEPTAL were reported. Should a patient develop a skin reaction with TRILEPTAL, consideration should be given to discontinuing TRILEPTAL and prescribing another anti-epileptic medication Patients should be made aware of early toxic signs of the above-mentioned reactions, e.g. fever, rash, lesions in the mouth, bruising, purpura. They should be advised to contact their doctor immediately if such a reaction appears.

Alcohol: Caution should be exercised if alcohol is taken in combination with TRILEPTAL therapy, due to a possible additive sedative effect.

Withdrawal: TRILEPTAL should be withdrawn gradually to minimise the potential of increased seizure frequency. If TRILEPTAL has to be discontinued abruptly, e.g. owing to severe adverse reactions, the change-over to another anti-epileptic preparation should be effected under cover of suitable medication (e.g. diazepam i.v., rectal; phenytoin i.v.) and under close supervision. TRILEPTAL oral suspension contains ethanol, less than 100 mg per dose. It contains parabenes which may cause allergic reactions (possibly delayed). It contains sorbitol and, therefore, should not be administered to patients with rare hereditary problems of fructose intolerance.

Suicidal ideation and behaviour: Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications (see u201c Special precautionsu201d).

In vitro and in vivo studies demonstrate that TRILEPTAL has a low potential for drug interactions. Enzyme inhibition: TRILEPTAL was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other medicinal products. The results demonstrate that TRILEPTAL and its pharmacologically active metabolite (the monohydroxy derivative, MHD) have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19. Therefore, interactions could arise when co-administering high doses of TRILEPTAL with medicinal products that are metabolised by CYP2C19 (e.g. phenobarbitone, phenytoin). In some patients treated with TRILEPTAL and medicinal products metabolized via CYP2C19 a reduction of the co-administered medicinal product might be necessary.

Enzyme induction: In vitro, the UDP-glucuronyl transferase level was increased, indicating induction of this enzyme. An increase of 22 % with MHD and 47 % with TRILEPTAL were observed. TRILEPTAL and MHD are weak inducers of UDP-glucuronyl transferase and therefore, in vivo they are unlikely to have an effect on medicinal products which are mainly eliminated by conjugation through the UDP-glucuronyl transferases (e.g. valproic acid, lamotrigine). Even in view of the weak induction potential of TRILEPTAL and MHD, a higher dose of concomitantly used medicinal products which are metabolized via CYP3A4 or via conjugation (UDPGT) may be necessary. In case of discontinuation of TRILEPTAL therapy, a dose reduction of the concomitant medication may be necessary. Induction studies conducted with human hepatocytes confirmed TRILEPTAL and MHD as weak inducers of isoenzymes of the 2B and 3A4 CYP sub-family. The induction potential of TRILEPTAL /MHD on other CYP isoenzymes is not known. TRILEPTAL and MHD induce in vitro and in vivo, a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives, and antiepileptic medicinal products (e.g. carbamazepine) resulting in a lower plasma concentration of these medicinal products (see below). Such level of decrease in plasma concentrations may also be observed in other medicines mainly metabolized by CYP3A4 and CYP3A5, for example immunosuppressants (e.g. ciclosporin).

Antiepileptic medicinal products: Potential interactions between TRILEPTAL and other antiepileptic medicinal products (AEMPs) were assessed in clinical studies. The effect of these interactions on mean AUCs and C min are summarised in the following table. Summary of antiepileptic medicinal products interactions with TRILEPTAL AEMP Influence of TRILEPTAL on AEMP Influence of AEMP on MHD Co-administerd Concentration Concentration Carbamazepine 0 - 22 % decrease (30 % increase of carbamazepine- epoxide) 40 % decrease Clobazam Not studied No influence Felbamate Not studied No influence Phenobarbitone 14 - 15 % increase 30 - 31 % decrease Phenytoin 0 - 40 % increase 29 - 35 % decrease Valproic acid No influence 0 - 18 % decrease

In vivo, the plasma levels of phenytoin increased by up to 40 %, when TRILEPTAL was given at doses above 1200 mg/day. Therefore, when using doses of TRILEPTAL greater than 1200 mg/day during adjunctive therapy, a decrease in the dose of phenytoin may be required. The increase of phenobarbitone level, however, is small (15 %) when given with TRILEPTAL. Strong inducers of cytochrome P450 enzymes (i.e. carbamazepine, phenytoin and phenobarbitone) have been shown to decrease the plasma levels of MHD (29-40 %). No auto-induction has been observed with TRILEPTAL.

Hormonal contraceptives: TRILEPTAL was shown to have an influence on the two components, ethinylestradiol (EE) and levonorgestrel (LNG), of an oral contraceptive. The mean AUC values of EE and LNG were decreased by 48-52 % and 32-52 % respectively. Studies with other oral or implant contraceptives have not been conducted. Therefore, concurrent use of TRILEPTAL with hormonal contraceptives may render these contraceptives less effective (see u201cSpecial precautionsu201d).

Calcium antagonists: After repeated co-administration of TRILEPTAL, the AUC values of felodipine were lowered by 28 %. However, the plasma levels remained in the recommended therapeutic range. On the other hand, verapamil produced a decrease of 20 % of the plasma levels of MHD. This decrease in plasma levels of MHD is not considered to be of clinical relevance.

Other medicinal products interactions: Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD, whereas viloxazine produced minor changes in the MHD plasma levels (about 10 % higher after repeated co-administration). Results with warfarin show no evidence of interaction with either single or repeated doses of TRILEPTAL. The use of TRILEPTAL is contra-indicated in combination with monoamine-oxidase inhibitors (MAOIs). Before administering TRILEPTAL, MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits.

Data on a limited number of pregnancies indicate that TRILEPTAL may cause serious birth defects (e.g. cleft palate) when administered during pregnancy. In animal studies, increased embryo mortality, delayed growth and malformations were observed. Taking these data into consideration: - If women receiving TRILEPTAL become pregnant, plan to become pregnant, or if the need to initiate treatment with TRILEPTAL arises during pregnancy, the medicinal productsu2019 potential benefits must be carefully weighed against the potential risk of foetal malformations. (e.g. cleft palate). This is particularly important during the first three months of pregnancy. - Minimum effective doses should be given. - In women of childbearing age, TRILEPTAL should be administered as monotherapy, whenever possible. - Patients should be counseled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening. - During pregnancy, antiepileptic treatment must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.

Monitoring and prevention: Antiepileptic medicinal products such as TRILEPTAL may contribute to folic acid deficiency, a possible contributory cause of foetal abnormality. Folic acid supplementation is recommended before and during pregnancy.

Due to physiological changes during pregnancy, plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxyderivative (MHD), may gradually decrease throughout pregnancy. It is recommended that clinical response should be monitored carefully in women receiving TRILEPTAL treatment during pregnancy and determination of changes in MHD plasma concentrations should be considered to ensure that adequate seizure control is maintained throughout pregnancy. Postpartum MHD plasma levels may also be considered for monitoring especially in the event that medication was increased during pregnancy.

In the newborn child: Bleeding disorders in the newborn caused by antiepileptic agents have been reported. As a precaution, vitamin K 1 should be administered as a preventive measure in the last few weeks of pregnancy and to the newborn. TRILEPTAL and its active metabolite (MHD) cross the placenta. Neonatal and maternal plasma MHD concentrations were similar in one case.

Use during lactation: TRILEPTAL and its active metabolite are excreted in breast milk. A milk-to-plasma concentration ratio of 0,5 were found for both. The effects on the infant exposed to TRILEPTAL by this route are unknown. Therefore, breast-feeding while taking TRILEPTAL is not recommended.

The use of TRILEPTAL has been associated with adverse reactions such as dizziness or somnolence. Therefore, patients should be advised that their physical and/or mental abilities required for operating machinery or driving a car might be impaired.

The most commonly reported adverse reactions are somnolence, headache, dizziness, diplopia, nausea, vomiting and fatigue occurring in more than 10 % of patients. In clinical trials, adverse events (AEs) were generally mild to moderate in severity, of transient nature and occurred predominantly at the start of treatment. The analysis of the undesirable effect profile by body system is based on AEs from clinical trials assessed as related to TRILEPTAL. In addition, clinically meaningful reports on adverse experiences from named patient programs and post-marketing experience were taken into account. Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common: ( u2265 1/10); common: ( u2265 1/100, - <1/10); uncommon: ( u2265 1/1,000, - <1/100); rare: ( u2265 1/10,000, - <1/1,000); very rare: (<1/10,000), including isolated reports.

Blood and lymphatic system disorders Uncommon Leucopenia. Very rare Bone marrow depression, agranulocytosis, aplastic anaemia, pancytopenia, neutropenia, and thrombocytopenia.

Immune system disorders Very rare Hypersensitivity (including multi-organ hypersensitivity) characterised by features such as rash, fever. Other organs or systems may be affected such as blood and lymphatic system (e.g. eosinophilia, thrombocytopenia, leucopenia, lymphadenopathy, splenomegaly); liver (e.g. abnormal liver function tests, hepatitis); muscle and joints (e.g. joint swelling, myalgia, arthralgia); nervous system (e.g. hepatic encephalopathy); kidney (e.g. proteinuria, nephritis interstitial, renal failure); lungs (e.g. dyspnoea, pulmonary oedema, asthma, bronchospasms, interstitial lung disease); angioedema. Anaphylactic reactions.

Metabolism and nutrition disorders Common Hyponatraemia. Very rare Hyponatraemia associated with signs and symptoms such as seizures, confusion, depressed level of consciousness, encephalopathy (see also Nervous system disorders for further undesirable effects), vision disorders (e.g. blurred vision), vomiting, and nausea. Folic acid deficiency. Hypothyroidism

Psychiatric disorders Common Confusional state, depression, apathy, agitation (e.g. nervousness), affect lability.

Nervous system disorders Very common Somnolence, headache, dizziness.

Eye disorders Very common Diplopia. Common Vision blurred, visual disturbance.

Ear and labyrinth disorders Common Vertigo.

Cardiac disorders Vascular disorders Hypertension Very rare Arrhythmia, atrioventricular block.

Gastrointestinal disorders Very common Nausea, vomiting. Common Diarrhoea, constipation, abdominal pain. Very rare Pancreatitis and/or lipase and/or amylase increase.

Hepato-biliary disorders Very rare Hepatitis.

Skin and subcutaneous tissue disorders Common Rash, alopecia, acne. Uncommon Urticaria. Very rare Angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyellu2019s syndrome), erythema multiforme.

Musculoskeletal, connective tissue and bone disorders Very rare Systemic lupus erythematosus.

General disorders and administration site conditions Very common Fatigue. Common Asthenia.

Investigations Uncommon Hepatic enzymes increased, blood alkaline phosphatase increased.

Very rarely clinically significant hyponatraemia (sodium < 125 mmol/L) can develop during TRILEPTAL use. It generally occurred during the first 3 months of treatment with TRILEPTAL, although there were patients who first developed a serum sodium < 125 mmol/L more than 1 year after initiation of therapy (see section u2018 SPECIAL PRECAUTIONS u2019). In clinical trials in children aged 1 month to less than 4 years, the most commonly reported adverse reaction was somnolence occurring in approximately 11 % of patients. Adverse reactions occurring at an incidence of u2265 1 % - <10 % (common) were: ataxia, irritability, vomiting, lethargy, fatigue, nystagmus, tremor, decreased appetite, and blood uric acid increased.

Adverse drug reactions from spontaneous reports and literature cases (frequency not known) The following adverse drug reactions have been derived from post-marketing experience with TRILEPTAL via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Immune system disorders: Drug Rash with Eosinophilia and Systemic Symptoms (DRESS). Skin and subcutaneous tissue disorders: Acute Generalised Exanthematous Pustulosis (AGEP). Musculoskeletal, connective tissue and bone disorders: There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with TRILEPTAL. The mechanism by which oxcarbazepine affects bone metabolism has not been identified.

Symptoms of overdose include somnolence, dizziness, nausea, vomiting, hyperkinesia, hyponatraemia, ataxia and nystagmus. There is no specific antidote. Treatment is symptomatic and supportive. Removal of the drug by gastric lavage and/or inactivation by administering activated charcoal should be considered.